This invention relates to compounds which may be useful for treating diseases caused or exacerbated by H3 receptor activity, pharmaceutical compositions containing the compounds, preparation of the compounds, and methods of treatment using the compounds.
Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) which are commonly treated with antagonists of histamine or xe2x80x9cantihistamines.xe2x80x9d It has also been established that histamine receptors exist in at least two distinct types, referred to as H1 and H2 receptors.
A third histamine receptor (the H3 receptor) is believed to play a role as a neurotransmitter in the central nervous system, where it is thought to be disposed presynaptically on histaminergic nerve endings (Nature, 302, 832-837 (1983)). The existence of the H3 receptor has been confirmed by the development of selective H3 agonists and antagonists (Nature, 327, 117-123 (1987)) and has subsequently been shown to regulate the release of other neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs and gastrointestinal tract.
Thus, it is anticipated that H3 receptor antagonists may have therapeutic utility for a number of indications such as asthma, ardiovasular disorders, gastrointestinal disorders, inflammation, sedatives, sleep regulators, anticonvulsants, and antidepressants.
In its principle embodiment, this invention discloses a compound selected from the group consisting of a compound of formula (I) 
a compound of formula (II) 
a compound of formula (III) 
and
a compound of formula (IV) 
or pharmaceutically acceptable salts thereof wherein,
L1 is absent or optionally substituted cycloalkyl or optionally substituted cycloalkylalkylene;
L2 is absent or alkylene, optionally substituted with aryl;
with the proviso that at least one of L1 or L2 is not absent;
n is one or two;
Q1 is absent or selected from the group consisting of xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94SO2xe2x80x94, and xe2x80x94C(xe2x95x90Nxe2x80x94R9)xe2x80x94;
Q2 is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94, and acetylene;
R1, R2, and R3 are independently hydrogen or alkyl;
R4 is selected from the group consisting of alkoxy, amino, optionally substituted aryl, aryloxy, optionally substituted cycloalkyl, cycloalkoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and xe2x80x94W1xe2x80x94C(R11)(R11a)xe2x80x94NR12R12a;
R5 is hydrogen or R4;
with the proviso that Q1 is not absent in compounds of formula (I) and when Q1 is carbonyl in formula (I), then R4 is not alkyl; and
with the proviso that when R5 is hydrogen, Q1 is absent or xe2x80x94C(xe2x95x90O)xe2x80x94;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, azido, carboxaldehyde, carboxyl, cyano, halo, hydroxyl, nitro, perfluoroalkyl, and perfluoroalkoxy; or
R6 and R7 are on adjacent carbon atoms and taken together are xe2x80x94OCH2C(O)xe2x80x94;
R8 is selected from the group consisting of alkyl, alkanoyl, alkoxy, alkoxycarbonyl, amino, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, carboxamido, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, halo, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, perfluoroalkyl, xe2x80x94C(H)(R3)xe2x80x94OR, and xe2x80x94C(R13)xe2x95x90Nxe2x80x94OR14;
R9 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, and hydroxyl;
R10 is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, and a nitrogen protecting group;
R11 and R11a are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, arylalkoxyalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl;
W1 is absent or is optionally substituted alkylene;
R12 and R12a are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl; or
R12 and R12a, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfone, dihydropyrimidinyl, tetrahydropyrimidinyl, and hexahydropyrimidinyl; or
W1 is an optionally substituted alkylene, and R11 and R12 together with the carbon and nitrogen atom to which they are respectively attached, form an optionally substituted heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl;
R13 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; and
R14 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, and an hydroxyl protecting group.
In another embodiment, this invention discloses a compound of formula (I) 
or a pharmaceutically acceptable salt thereof, wherein L1, L2, n, Q1, Q2, R1, R2, R3, R4, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a compound of formula (I), wherein L1 is absent and L2 is alkylene optionally substituted with aryl.
In another embodiment, this invention discloses a compound of formula (I), wherein n is one.
In another embodiment, this invention discloses a compound of formula (I), wherein n is two.
In another embodiment, this invention discloses a compound of formula (I), wherein Q1 is xe2x80x94C(xe2x95x90O)xe2x80x94.
In another embodiment, this invention discloses a compound of formula (I), wherein Q2 is xe2x80x94Oxe2x80x94.
In another embodiment, this invention discloses a compound of formula (I), wherein R1, R2, and R3 are hydrogen.
In another embodiment, this invention discloses a compound of formula (I), wherein R4 is 
wherein
one of R11 and R11a is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl; and
R12 and R12a are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R4 is depicted by the formula 
wherein
R11 is hydrogen; and
R11a, R12 and R12a are defined in the embodiment immediately above.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R4 is depicted by the formula 
wherein
R11 is hydrogen; and
R11a, R12 and R12a are defined in the embodiment proximally above.
In another embodiment, this invention discloses a compound of formula (I), wherein R4 is 
wherein
RE, and RF, and RG are independently selected from the group consisting of hydrogen, alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and ureido; or
RE and RF are taken together on the same carbon and are oxo or thioxo, and RG is selected from the group consisting of hydrogen, alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and ureido; and
x is one, two, three, or four.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R4 is depicted by the formula 
wherein
RE, RF, RG, and x are defined in the embodiment immediately above.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R4 is depicted by the formula 
wherein
RE, RF, RG, and x are defined are defined in the embodiment proximally above.
In another embodiment, this invention discloses a compound of formula (I), wherein R4 is 
wherein
RE, RF, RG and RH are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; alkoxy; alkanoyl; alkoxycarbonyl; alkylsulfonyl; amino; aminosulfonyl; azido; carboxamido; carboxy; cyano; halo; hydroxyl; oxo; thioxo; nitro; a nitrogen protecting group; perfluoroalkyl; perfluoroalkoxy; aryloyl; arylsulfonyl; heteroaryloyl; heteroarylsulfonyl; heterocycloalkyloyl; heterocycloalkylsulfonyl; phenyl; a heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and a heterocycloalkyl selected from the group consisting of tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl,
wherein the phenyl, the heteroaryl, and the heterocycloalkyl groups can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy; or
RE and RF are attached to the same carbon and are oxo or thioxo; and RG and RH are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; alkoxy; alkanoyl; alkoxycarbonyl; alkylsulfonyl; amino; aminosulfonyl; azido; carboxamido; carboxy; cyano; halo; hydroxyl; oxo; thioxo; nitro; a nitrogen protecting group; perfluoroalkyl; perfluoroalkoxy; aryloyl; arylsulfonyl; heteroaryloyl; heteroarylsulfonyl; heterocycloalkyloyl; heterocycloalkylsulfonyl; phenyl; a heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and a heterocycloalkyl selected from the group consisting of tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl,
wherein the phenyl, the heteroaryl, and the heterocycloalkyl groups can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy; and
y is one, two, or three.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R4 is depicted by the formula 
wherein
RE, RF, RG, RH, and y are defined in the embodiment immediately above.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R4 is depicted by the formula 
wherein
RE, RF, RG, RH, and y are defined in the embodiment proximally above.
In another embodiment, this invention discloses a compound of formula (I), wherein R4 is 
wherein
one of R11 and R11a is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl;
R12 and R12a are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl; and
W1 is alkylene.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R4 is depicted by the formula 
wherein
R11, R11a, R12, R12a, and W1 are defined in the embodiment immediately above. In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R4 is depicted by the formula 
R11, R11a, R12, R12a, and W1 are defined in the embodiment proximally above. In another embodiment, this invention discloses a compound of formula (I), wherein R4 is 
wherein
W1 is alkylene;
R11a is hydrogen or alkyl;
R12a is selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl; and
R11 and R12, together with the carbon and nitrogen atom to which they are respectively attached, are a heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl, wherein the heterocycloalkyl ring formed by R11 and R12 together can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl; alkenyl; alkynyl; alkoxy; alkanoyl; alkoxycarbonyl; alkylsulfonyl; amino; aminosulfonyl; azido; carboxamido; carboxy; cyano; halo; hydroxyl; oxo; thioxo; nitro; a nitrogen protecting group; perfluoroalkyl; perfluoroalkoxy; aryloyl; arylsulfonyl; heteroaryloyl; heteroarylsulfonyl; heterocycloalkyloyl; heterocycloalkylsulfonyl; phenyl; a heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and a heterocycloalkyl selected from the group consisting of tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl,
wherein the phenyl, the heteroaryl, and the heterocycloalkyl groups can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R4 is depicted by the formula 
wherein
R11, R11a, R12, R12a, and W1 are defined in the embodiment immediately above.
In another embodiment, this invention discloses a compound of formula (I), wherein the relative stereochemistry of R4 is depicted by the formula 
wherein
R11, R11a, R12, R12a, and W1 are defined in the embodiment proximally above. In another embodiment, this invention discloses a compound of formula (I), wherein R6 is hydrogen.
In another embodiment, this invention discloses a compound of formula (I), wherein R7 is hydrogen or halo.
In another embodiment, this invention discloses a compound of formula (I), wherein R8 is selected from the group consisting of alkanoyl, aryl, carboxamido, cycloalkyloyl, cyano, halo, heteroaryl, and perfluoroalkyl.
In another embodiment, this invention discloses a compound of formula (I), wherein R8 is cyclopropanoyl.
In another embodiment, this invention discloses a compound of formula (I), wherein R8 is 4-cyanophen-4xe2x80x2-yl.
In another embodiment, this invention discloses a compound of formula (I), wherein R8 is optionally substituted heteroaryl of the formula 
wherein
RJ is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkoxyalkoxyalkyl, aminoalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocycloalkyl, alkoxycarbonyl, and perfluoroalkyl.
In another embodiment, this invention discloses a compound of formula (II), 
or a pharmaceutically acceptable salt thereof, wherein
L1, L2, Q1, Q2, n, R5, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a compound of formula (II), wherein L1 is absent and L2 is alkylene, optionally substituted with aryl.
In another embodiment, this invention discloses a compound of formula (II), wherein Q1 is absent or is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94SO2xe2x80x94.
In another embodiment, this invention discloses a compound of formula (II), wherein Q2 is xe2x80x94Oxe2x80x94 or acetylene.
In another embodiment, this invention discloses a compound of formula (II), wherein n is one.
In another embodiment, this invention discloses a compound of formula (II), wherein R5 is selected from the group consisting of hydrogen, alkyl, alkoxy, amino, aryl, heteroaryl, cycloalkyl, cycloalkoxy, aryloxy, and heterocycloalkyl.
In another embodiment, this invention discloses a compound of formula (II), wherein R5 is 
wherein
one of R11 and R11a is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl; and
R12 and R12a are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl.
In another embodiment, this invention discloses a compound of formula (II), the relative stereochemistry of R5 is depicted by the formula 
wherein
R11 is hydrogen; and
R11a, R12 and R12a are defined in the embodiment immediately above.
In another embodiment, this invention discloses a compound of formula (II), wherein the relative stereochemistry of R5 is depicted by the formula 
wherein
R11 is hydrogen; and
R11a, R12 and R12a are defined in the embodiment proximally above.
In another embodiment, this invention discloses a compound of formula (II), wherein R5 is 
wherein
RE, and RF, and RG are independently selected from the group consisting of hydrogen, alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and ureido; or
RE and RF are taken together on the same carbon and are oxo or thioxo, and RG is selected from the group consisting of hydrogen, alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, and ureido; and
x is one, two, three, or four.
In another embodiment, this invention discloses a compound of formula (II), wherein the relative stereochemistry of R5 is depicted by the formula 
wherein
RE, RF, RG, and x are defined in the embodiment immediately above.
In another embodiment, this invention discloses a compound of formula (II), wherein the relative stereochemistry of R5 is depicted by the formula 
wherein
RE, RF, RG, and x are defined in the embodiment proximally above.
In another embodiment, this invention discloses a compound of formula (II), wherein R5 is 
wherein
one of R11 and R11a is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl;
R12 and R12a are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl; and
W1 is alkylene.
In another embodiment, this invention discloses a compound of formula (II), wherein the relative stereochemistry of R5 is depicted by the formula 
wherein
R11, R11a, R12, R12a, and W1 are defined in the embodiment immediately above.
In another embodiment, this invention discloses a compound of formula (II), wherein the relative stereochemistry of R5 is depicted by the formula 
wherein
R11, R11a, R12, R12a, and W1 are defined in the embodiment proximally above. In another embodiment, this invention discloses a compound of formula (II), wherein R6 and R7 are hydrogen.
In another embodiment, this invention discloses a compound of formula (II), wherein R8 is alkanoyl or cycloalkyloyl.
In another embodiment, this invention discloses a compound of formula (II), wherein R8 is cyclopropanoyl.
In another embodiment, this invention discloses a compound of formula (III) 
or a pharmaceutically acceptable salt thereof, wherein
L1, L2, Q1, Q2, n, R5, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a compound of formula (III), wherein L1 is absent and L2 is alkylene, optionally substituted with aryl.
In another embodiment, this invention discloses a compound of formula (III), wherein Q1 is absent or is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94SO2xe2x80x94.
In another embodiment, this invention discloses a compound of formula (III), wherein Q2 is xe2x80x94Oxe2x80x94 or acetylene.
In another embodiment, this invention discloses a compound of formula (III), wherein n is one.
In another embodiment, this invention discloses a compound of formula (III), wherein R5 is selected from the group consisting of hydrogen, alkoxy, and aryl.
In another embodiment, this invention discloses a compound of formula (III), wherein R5 is 
wherein
one of R11 and R11a is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl; and
R12 and R12a are independently selected from the group consisting of hydrogen,
alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl.
In another embodiment, this invention discloses a compound of formula (III), wherein the relative stereochemistry of R5 is depicted by the formula 
wherein
R11, R11a, R12 and R12a are defined in the embodiment immediately above.
In another embodiment, this invention discloses a compound of formula (III), wherein the relative stereochemistry of R5 is depicted by the formula 
wherein
R11, R11a, R12 and R12a defined in the embodiment proximally above.
In another embodiment, this invention discloses a compound of formula (III), wherein R6 and R7 are hydrogen.
In another embodiment, this invention discloses a compound of formula (III), wherein R8 is cyclopropanoyl.
In another embodiment, this invention discloses a compound of formula (III), wherein R8 is 4-cyanophen-4xe2x80x2-yl.
In another embodiment, this invention discloses a compound of formula (IV) 
or a pharmaceutically acceptable salt thereof, wherein
L1, L2, Q1, Q2, n, R5, R6, R7 and R8 are defined above.
In another embodiment, this invention discloses a compound of formula (IV), wherein L1 is absent.
In another embodiment, this invention discloses a compound of formula (IV), wherein L2 is alkylene.
In another embodiment, this invention discloses a compound of formula (IV), wherein Q1 is xe2x80x94C(xe2x95x90O)xe2x80x94.
In another embodiment, this invention discloses a compound of formula (IV), wherein Q2 is xe2x80x94Oxe2x80x94 or acetylene.
In another embodiment, this invention discloses a compound of formula (IV), wherein R5 is alkoxy.
In another embodiment, this invention discloses a compound of formula (IV), wherein R5 is 
wherein
one of R11 and R11a is hydrogen or alkyl, and the other is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, amino, aminoalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, and ureidoalkyl; and
R12 and R12a are independently selected from the group consisting of hydrogen, alkyl, alkanoyl, alkylsulfonyl, a nitrogen protecting group, aminosulfonyl, optionally substituted aryl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, optionally substituted heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylsulfonyl, optionally substituted heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloyl, and heterocycloalkylsulfonyl.
In another embodiment, this invention discloses a compound of formula (IV), wherein the relative stereochemistry of R5 is depicted by the formula 
wherein
R11, R11a, R12 and R12a defined in the embodiment immediately above.
In another embodiment, this invention discloses a compound of formula (IV), wherein the relative stereochemistry of R5 is depicted by the formula 
wherein
R11, R11a, R12 and R12a defined in the embodiment proximally above.
In another embodiment, this invention discloses a compound of formula (IV), wherein R6 and R7 are hydrogen.
In another embodiment, this invention discloses a compound of formula (IV), wherein R8 is cyclopropanoyl.
In another embodiment, this invention discloses a method for antagonizing the H3 receptor comprising administering a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1, L2, n, Q1, Q2, R1, R2, R3, R4, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a method for antagonizing the H3 receptor comprising administering a pharmaceutically acceptable amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein L1, L2, n, Q1, Q2, R5, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a method for antagonizing the H3 receptor comprising administering a pharmaceutically acceptable amount of a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein L1, L2, n, Q1, Q2, R5, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a method for antagonizing the H3 receptor comprising administering a pharmaceutically acceptable amount of a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein L1, L2, Q1, Q2, R5, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a method for treating disorders or diseases which may be alleviated by H3 receptor activity in a mammal comprising administering to the mammal in recognized need of such treatment a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1, L2, n, Q1, Q2, R1, R2, R3, R4, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a method for treating disorders or diseases which may be alleviated by H3 receptor activity in a mammal comprising administering to the mammal in recognized need of such treatment a pharmaceutically acceptable amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein L1, L2, n, Q1, Q2, R5, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a method for treating disorders or diseases which may be alleviated by H3 receptor activity in a mammal comprising administering to the mammal in recognized need of such treatment a pharmaceutically acceptable amount of a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein L1, L2, n, Q1, Q2, R5, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a method for treating disorders or diseases which may be alleviated by H3 receptor activity in a mammal comprising administering to the mammal in recognized need of such treatment a pharmaceutically acceptable amount of a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein L1, L2, Q1, Q2, R5, R6, R7, and R8 are defined above.
In another embodiment, this invention discloses a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1, L2, n, Q1, Q2, R1, R2, R3, R4, R6, R7, and R8 are defined above, and a pharmaceutically acceptable carrier.
In another embodiment, this invention discloses a composition comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein L1, L2, n, Q1, Q2, R5, R6, R7, and R8 are defined above, and a pharmaceutically acceptable carrier.
In another embodiment, this invention discloses a composition comprising a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein L1, L2, n, Q1, Q2, R5, R6, R7, and R8 are defined above, and a pharmaceutically acceptable carrier.
In another embodiment, this invention discloses a composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein L1, L2, Q1, Q2, R5, R6, R7, and R8 are defined above, and a pharmaceutically acceptable carrier.
This invention discloses series of asymmetrically N,Nxe2x80x2-disubstituted 1,4-piperazines (compounds of formula (I), wherein n is one), 1,4-diazepanes (compounds of formula (I), wherein n is two), (1S, 4S)-2,5-diazabicyclo(3.2.1)heptanes (compounds of formula (II)), (1R,4R)-2,5-diazabicyclo(2.2.1)heptanes (compounds of formula (III)), and 3,8-diazabicyclo(3.2.1)octanes (compounds of formula (IV)) which may be useful for antagonizing the H3 receptor and may be therefore useful for treating diseases caused or exacerbated by H3 receptor activity.
Definition of Terms
All references cited herein are incorporated by reference. In the case of inconsistencies, the instant disclosure, including definitions, will prevail.
As used for this invention, the following terms have the meanings ascribed.
The term xe2x80x9cacetylenexe2x80x9d as used herein refers to ethyne.
The term xe2x80x9calkanoyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a monovalent straight or branched chain hydrocarbon radical having from two to ten carbon atoms and at least one carbon-carbon double bond.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, connected to the parent molecular moiety through an oxygen atom.
The term xe2x80x9calkoxyalkoxy,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through another alkoxy group, as defined herein.
The term xe2x80x9calkoxyalkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxyalkoxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through an alkyl group as defined herein.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a monovalent straight or branched chain saturated hydrocarbon radical having from one to ten carbon atoms.
The term xe2x80x9calkylene,xe2x80x9d as used herein, refers to a divalent straight or branched chain saturated hydrocarbon diradical having from one to ten carbon atoms.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a monovalent straight or branched chain hydrocarbon radical having from two to ten carbon atoms and at least one carbon-carbon triple bond. The alkynyl groups of this invention can be optionally substituted with a substituent selected from the group consisting of alkenyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl.
The term xe2x80x9camino,xe2x80x9das used herein, refers to xe2x80x94NH2 or a derivative thereof formed by independent replacement of one or both hydrogen atoms thereon with a substituent or substituents independently selected from the group consisting of alkanoyl, alkenyl, alkyl, alkylsulfonyl, alkynyl, aminosulfonyl, aryl, arylalkenyl, arylalkyl, aryloyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkyloyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloyl, heteroarylalkenyl, heteroarylsulfonyl, heterocycloalkylalkyl, heterocycloalkyloyl, heterocycloalkylsulfonyl, a nitrogen protecting group, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl.
The term xe2x80x9caminoalkyl,xe2x80x9d as used herein, refers to an amino group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
The terms xe2x80x9camino protecting group,xe2x80x9d and xe2x80x9cnitrogen protecting group,xe2x80x9d as used herein, refer to selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures. Examples of amino protecting groups include trichloroethoxycarbonyl, benzyloxycarbonyl (Cbz), chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-butoxycarbonyl (Boc), para-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, phthaloyl, succinyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triphenylsilyl, and the like. Preferred nitrogen protecting groups of this invention are benzyloxycarbonyl (Cbz), and tert-butoxycarbonyl (Boc).
The term xe2x80x9caminosulfonyl,xe2x80x9d as used herein, refers to an amino group, as defined herein, attached to the parent molecular moiety through a sulfonyl group.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a six-membered aromatic carbocyclic ring. The aryl groups of this invention are exemplified by phenyl.
The term xe2x80x9carylalkenyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, attached to the parent molecular moiety through an alkenyl group, as defined herein.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. The aryl part or parts of the arylalkyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxyl, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9carylalkoxyalkyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, attached to the parent molecular moiety through an alkoxyalkyl group, as defined herein.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. The aryl part or parts of the arylalkyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxyl, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9caryloyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, attached to the parent molecular moiety through a carbonyl group. The aryl part of the aryloyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, aryloxy, azido, carboxaldehyde, carboxamido, carboxyl, cyano, cycloalkyl, halo, hydroxyl, methylenedioxy, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9carylsulfonyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, attached to the parent molecular moiety through a sulfonyl group. The aryl part or parts of the arylalkyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxyl, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9cazido,xe2x80x9d as used herein, refers to xe2x80x94N3.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to xe2x80x94(Cxe2x95x90O)xe2x80x94.
The term xe2x80x9ccarboxaldehyde,xe2x80x9d as used herein, refers to xe2x80x94CHO.
The term xe2x80x9ccarboxamido,xe2x80x9d as used herein, refers to an amino group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein.
The terms xe2x80x9ccarboxylxe2x80x9d or xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to xe2x80x94CO2H or a derivative thereof formed by replacement of the hydrogen atom thereon with a carboxyl protecting group. The terms carboxy protecting group, and carboxyl protecting group, as used herein refer to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. In addition, a carboxy-protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent. Representative carboxy-protecting groups are methyl, ethyl or tert-butyl; benzyl; 4-methoxybenzyl; nitrobenzyl; dimethylaminoethyl; pivaloyloxymethyl, propionyloxymethyl; benzoyloxyethyl; methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl; tert-butyloxycarbonyloxymethyl; tert-butyloxycarbonylaminomethyl; methylaminocarbonylaminomethyl; acetylaminomethyl; 4-methylpiperazinylcarbonyloxymethyl; dimethylaminocarbonylmethyl; (5-tert-butyl-2-oxo-1,3-dioxolen-4-yl)methyl; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to xe2x80x94CN.
The term xe2x80x9ccyanoalkyl,xe2x80x9d as used herein, refers to a cyano group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
The term xe2x80x9ccycloalkoxy,xe2x80x9d as used herein, refers to cycloalkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. The cycloalkyl part of the cycloalkoxy can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, amino, hydroxyl, and oxo.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a monovalent saturated cyclic hydrocarbon radical having three to seven carbon atoms.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. The cycloalkyl part or parts of the cycloalkylalkyl can be optionally substituted with one, two, or three a groups independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, amino, aryl, azido, carboxaldehyde, carboxyl, halo, hydroxyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, oxo, perfluoroalkoxy, perfluoroalkyl, thioxo, and uriedo.
The term xe2x80x9ccycloalkylene,xe2x80x9d as used herein, refers to a divalent saturated cyclic hydrocarbon diradical having from three to seven carbon atoms.
The term xe2x80x9ccycloalkyloyl,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. The cycloalkyl part of the cycloalkyloyl can be optionally substituted with one, two, or three groups independently selected from the consisting of alkoxy, alkoxycarbonyl, alkyl, amino, aryl, azido, carboxaldehyde, carboxyl, halo, hydroxyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, oxo, perfluoroalkoxy, perfluoroalkyl, thioxo, and uriedo.
The term xe2x80x9ccycloalkylsulfonyl,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein. The cycloalkyl part of the cycloalkylsulfonyl can be optionally substituted with one, two, or three groups independently selected from the consisting of alkoxy, alkoxycarbonyl, alkyl, amino, aryl, azido, carboxaldehyde, carboxyl, halo, hydroxyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, oxo, perfluoroalkoxy, perfluoroalkyl, thioxo, and uriedo.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalide,xe2x80x9d as used herein, refer to F, Cl, Br, or I.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, refers to a cyclic, aromatic five-or six-membered ring having at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur. The five-membered rings have two double bonds, and the six-membered rings have three double bonds. Heteroaryls of this invention are exemplified by furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The heteroaryl groups of this invention are connected through a carbon atom in the ring.
The term xe2x80x9cheteroarylalkenyl,xe2x80x9d as used herein, refers to a heteroaryl group, as defined herein, attached to the parent molecular moiety through an alkenyl group, as defined herein.
The term xe2x80x9cheteroarylalkyl,xe2x80x9d as used herein, refers to a heteroaryl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. The heteroaryl part or of the heteroarylalkyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9cheteroaryloyl,xe2x80x9d as used herein, refers to a heteroaryl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. The heteroaryl part of the heteroaryloyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9cheteroarylsulfonyl,xe2x80x9d as used herein, refers to a heteroaryl group, as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein. The heteroaryl part of the heteroarylsulfonyl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9cheterocycloalkyl,xe2x80x9d as used herein, refers to a non-aromatic four-, five-or six-membered ring having at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur. The four-membered rings have zero double bonds, the five-membered rings have zero or one double bond and the six-membered rings have zero, one or two double bonds. Heterocycloalkyls of this invention are exemplified by tetrahydrofuranyl, pyrrolinyl, dioxolanyl, imidazolinyl, pyrazolinyl, pyrazolidinyl, pyranyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, azepanyl, dioxanyl, morpholinyl, dithianyl, dihydropyridazinyl, tetrahydropyridazinyl, dihydropyrazinyl, tetrahydrohydropyrazinyl, and piperazinyl. The heterocycloalkyl groups of this invention can be connected through either a carbon atom or a nitrogen atom in the ring.
The term xe2x80x9cheterocycloalkylalkyl,xe2x80x9d as used herein, refers to a heterocycloalkyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. The heterocycloalkyl part or parts of the heterocycloalkylalkyl can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9cheterocycloalkylalkyloyl,xe2x80x9d as used herein, refers to a heterocycloalkylalkyl group attached to the parent molecular moiety through a carbonyl group. The heterocycloalkyl part of the heterocycloalkylalkyloyl can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9cheterocycloalkyloyl,xe2x80x9d as used herein, refers to a heterocycloalkyl group attached to the parent molecular moiety through a carbonyl group. The heterocycloalkyl part of the heterocycloalkyloyl can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9cheterocycloalkyloylalkyl,xe2x80x9d as used herein, refers to a heterocycloalkyloyl group attached to the parent molecular moiety through an alkyl group. The heterocycloalkyl part of the heterocycloalkyloylalkyl can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9cheterocycloalkylsulfonyl,xe2x80x9d as used herein, refers to a heterocycloalkyl group attached to the parent molecular moiety through a sulfonyl group. The heterocycloalkyl part of the heterocycloalkylsulfonyl can be optionally substituted with one, two, or three groups independently selected from the group consisting of alkanoyl, alkoxy, alkoxycarbonyl, alkyl, amino, azido, carboxaldehyde, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The terms xe2x80x9chydroxyl,xe2x80x9d or xe2x80x9chydroxy,xe2x80x9d as used herein, refers to xe2x80x94OH or a derivative thereof formed by replacement of the hydrogen atom thereon with a hydroxyl protecting group.
The term xe2x80x9chydroxyl protecting group,xe2x80x9d as used herein, refers to selectively introducible and removable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures. Examples of hydroxyl protecting groups include groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, alkanoyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, tetrahydropyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, and triisopropylsilyl. Preferred hydroxyl protecting groups for this invention are alkanoyl, benzyl, methanesulfonyl, tert-butyldimethylsilyl, and tert-butyl.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to a hydroxyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein.
The term xe2x80x9cmethylenedioxy,xe2x80x9d as used herein, refers to a xe2x80x94OCH2Oxe2x80x94 group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms.
The term xe2x80x9cnitro,xe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
The term xe2x80x9coxo,xe2x80x9d as used herein, refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
The term xe2x80x9cperfluoroalkoxy,xe2x80x9d as used herein, refers to a perfluoroalkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9cperfluoroalkyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, in which all of the hydrogen atoms have been replaced with fluoride atoms.
The term xe2x80x9cpharmaceutically acceptable salt,xe2x80x9d as used herein, represents salts or zwitterionic forms of the compounds which are water or oil-soluble or dispersible and are suitable for ailments and or diseases without undue toxicity, irritation, and allergic response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting a free base group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; arylalkyl halides such as benzyl and phenethyl bromides. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulphuric, and phosphoric and organic acids such as oxalic, maleic, succinic, and citric.
Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxylic acid-containing group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts and nontoxic quaternary ammonia and amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributlyamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,Nxe2x80x2-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
The term xe2x80x9csubstituted alkylene,xe2x80x9d as used herein, refers to an alkylene group, as defined herein, substituted with one or two amino or aryl substituents. The aryl groups substituting the alkylene groups of this invention can be further substituted with one, two, three, four, or five substituents independently selected from the group consisting of amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, and hydroxy.
The term xe2x80x9csubstituted aryl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl; alkoxy; alkoxycarbonyl; alkenyl; alkyl; alkynyl; alkylsulfonyl; amino; aminosulfonyl; azido; carboxamido; carboxy; cyano; halo; hydroxyl; nitro; perfluoroalkoxy; perfluoroalkyl; aryloyl; arylsulfonyl; heteroaryloyl; heteroarylsulfonyl; heterocycloalkyloyl; heterocycloalkylsulfonyl; phenyl; a heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and a heterocycloalkyl selected from the group consisting of tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl. The phenyl, the heteroaryl, and the heterocycloalkyl groups substituting the aryl groups of this invention can also be optionally further substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, azido, carboxaldehyde, carboxamido, carboxyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9csubstituted cycloalkyl,xe2x80x9d as used herein, refers to an cycloalkyl group substituted with one, two, or three substituents independently selected from the group consisting of alkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, oxo, thioxo, and ureido.
The term xe2x80x9csubstituted cycloalkylene,xe2x80x9d as used herein, refers to a cycloalkylene group independently substituted with one or two fluoride or chloride substituents.
The term xe2x80x9csubstituted heteroaryl,xe2x80x9d as used herein, refers to a heteroaryl group substituted with one, two, or three, substituents independently selected from the group consisting of alkanoyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, alkynyl, amino, aminoalkyl, aminosulfonyl, aryl, arylalkyl, aryloyl, arylsulfonyl, azido, carboxamido, carboxy, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, halo, heteroaryl, heteroaryloyl, heteroarylsulfonyl, heterocycloalkyl, heterocycloalkyloyl, heterocycloalkyloylalkyl, heterocycloalkylsulfonyl, hydroxyl, nitro, perfluoroalkoxy, perfluoroalkyl, phenyl, or another heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and a heterocycloalkyl selected from the group consisting of tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl. The phenyl, the heteroaryl, and the heterocycloalkyl groups optionally substituting the heteroaryl groups of this invention can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, azido, carboxaldehyde, carboxamido, carboxyl, cyano, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9csubstituted heterocycloalkyl,xe2x80x9d as used herein, refers to a heterocycloalkyl group substituted with one, two, or three substituents independently selected from the group consisting of alkanoyl; alkoxy; alkoxycarbonyl; alkenyl; alkyl; alkylsulfonyl; alkynyl; amino; aminosulfonyl; aryloyl; arylsulfonyl; azido; carboxamido; carboxy; cyano; halo; heteroaryloyl; heteroarylsulfonyl; heterocycloalkyloyl; heterocycloalkylsulfonyl; hydroxyl; nitro; a nitrogen protecting group; oxo; perfluoroalkyl; perfluoroalkoxy; thioxo; phenyl; a heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and another heterocycloalkyl selected from the group consisting of tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl. The phenyl, the heteroaryl, and the heterocycloalkyl groups substituting the heterocycloalkyl groups of this invention, can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, azido, carboxaldehyde, carboxamido, carboxyl, halo, hydroxyl, perfluoroalkoxy, and perfluoroalkyl.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9cthioxo,xe2x80x9d as used herein, refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single sulfur atom.
The term xe2x80x9cthioalkoxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, connected to the parent molecular moiety through a sulfur atom.
The term xe2x80x9cureido,xe2x80x9d as used herein, refers to xe2x80x94NHC(O)NH2 or a derivative thereof formed by independent replacement of a hydrogen atom or hydrogen atoms thereon by a radical or radicals independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl.
The term xe2x80x9cureidoalkyl,xe2x80x9d as used herein, refers to a ureido group attached to the parent molecular moiety through an alkyl group.
Asymmetric centers can exist in the compounds of this invention. This invention contemplates stereoisomers and mixtures thereof. Individual stereoisomers of compounds are prepared by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described herein and resolved by techniques well-known in the art.
The compounds of this invention can exist as pharmaceutically acceptable prodrugs. The term pharmaceutically acceptable prodrug, as used herein, represents those prodrugs of the compounds of this invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of this invention.
The term xe2x80x9cprodrug,xe2x80x9d as used herein, represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.
In accordance to the methods of treatment of this invention, the compounds can be administered alone, in combination with, or in concurrent therapy with other H3 antagonists. When using the compounds as H3 antagonists, the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used. The compounds can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof. The term xe2x80x9cparenteralxe2x80x9d includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
Parenterally administered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents. The injectable preparation can also be an injectable solution or suspension in a diluent or solvent. Among the acceptable diluents or solvents employed are water, saline, Ringers solution, buffers, dilute acids or bases, dilute amino acid solutions, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
The H3 antagonistic activity of parenterally administered compounds can be prolonged by slowing their absorption. One way to slow the absorption of a particular compound is administering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound. The rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state. Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension. Yet another way to slow absorption of a particular compound is administering injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled.
Transdermal patches also provide controlled delivery of the compounds. The rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose. Capsules, tablets and pills can also comprise buffering agents; and tablets and pills can be prepared with enteric coatings or other release-controlling coatings. Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefor.
Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches. The compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers. These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable nonirritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina. Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.01 to about 500 mg/kg body weight or preferably from about 0.01 to about 100 mg/kg body weight. Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
Representative compounds of the invention include:
(4-(3-(4-((2S)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(2S)-1-(4-(3-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1-piperazinyl)-1-oxo-2-propanamine,
tert-butyl 2-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-2-oxoethylcarbamate,
2-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-2-oxoethanamine,
tert-butyl 3-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-3-oxopropylcarbamate,
3-(4-(3-( 4-bromophenoxy)propyl)-1-piperazin yl)-3-oxo-1-propanamine,
tert-butyl (1R)-2-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
(2R)-1-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-1-oxo-2-propanamine,
tert-butyl (1S)xe2x80x942-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
(2S)-1-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-1-oxo-2-propanamine,
tert-butyl (2S)-2-((4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
4-bromophenyl 3-(4-((2S)-pyrrolidinylcarbonyl) 1-piperazinyl)propyl ether
tert-butyl (2R)-2-((4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
4-bromophenyl 3-(4-((2R)-pyrrolidinylcarbonyl)-1-piperazinyl)propyl ether
tert-butyl (1R)-1-methyl-2-oxo-2-(4-(3-(4-(trifluoromethyl)phenoxy)propyl)-1-piperazinyl)ethylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-cyanophenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl 3-(4-(3-(4-cyano-3-fluorophenoxy)propyl)-1-piperazinyl)-3-oxopropylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-(aminocarbonyl)-3-fluorophenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
1-(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)ethanone,
N-((1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)acetamide,
ethyl (1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
N-((1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)cyclopropanecarboxamide,
tert-butyl (1R)-2-(4-((1R)-3-(4-acetylphenoxy)-1-methylpropyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (1S)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (2R)-2-((4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
tert-butyl (2S)-2-((4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
N-((1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)methanesulfonamide,
Nxe2x80x2-((1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-N,N-dimethylsulfamide,
1-(4-(3-(4-((methylamino)acetyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl 2-(4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)-2-oxoethylcarbamate,
1-(4-(3-(4-(3-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
1-(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1S)-1-((4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)carbonyl)-2-methylpropylcarbamate,
1-(4-(3-(4-((2S)-2-amino-3-methylbutanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1R)-1-((4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)carbonyl)-2-methylpropylcarbamate,
1-(4-(3-(4-((2R)-2-amino-3-methylbutanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1S)-1-((4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)carbonyl)-3-methylbutylcarbamate,
1-(4-(3-(4-((2S)-2-amino-4-methylpentanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1R)-1-((4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)carbonyl)-3-methylbutylcarbamate,
1-(4-(3-(4-((2R)-2-amino-4-methylpentanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1S)-1-((benzyloxy)methyl)-2-(4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)-2-oxoethylcarbamate,
1-(4-(3-(4-((2R)-2-amino-3-hydroxypropanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
1-(4-(3-(4-((2S)-2-amino-3-(benzyloxy)propanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1S)-2-(4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)-2-oxo-1-(4-pyridinylmethyl)ethylcarbamate,
1-(4-(3-(4-((2S)-2-amino-3-(4-pyridinyl)propanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1R)-2-(4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)-2-oxo-1-(4-pyridinylmethyl)ethylcarbamate,
1-(4-(3-(4-((2R)-2-amino-3-(4-pyridinyl)propanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1S)-2-(4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)-1-(1H-imidazol-4-ylmethyl)-2-oxoethylcarbamate,
1-(4-(3-(4-((2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl)-1-piperazinyl)propoxy)phenyl)-1-bexanone,
(4-(((3R)-3-(4-(3-aminopropanoyl)-1-piperazinyl)butyl)oxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R)-2-(4-((1R)-3-(4-(cyclopropylcarbonyl)phenoxy)-1-methylpropyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
(4-(((3R)-3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)butyl)oxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R)-2-(4-((1S)-3-(4-(cyclopropylcarbonyl)phenoxy)-1-methylpropyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
cyclopropyl(4-(((3R)-3-(4-((methylamino)acetyl)-1-piperazinyl)butyl)oxy)phenyl)methanone,
(4-(3-(4-((2R)-2-amino-3,3-dimethylbutanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-3,3-dimethylbutylcarbamate,
tert-butyl (1R)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-3,3-dimethylbutylcarbamate,
(4-(3-(4-((2R)-2-aminobutanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
cyclopropyl(4-(3-(4-((2R)-2-(methylamino)-3-phenylpropanoyl)-1-piperazinyl)propoxy)phenyl)methanone,
(4-(3-(4-((2R, 3S)-2-amino-3-hydroxybutanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
benzyl (1R)-1-(tert-butoxymethyl)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-2-oxoethylcarbamate,
(4-(3-(4-((2R)-2-amino-3-tert-butoxypropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R, 2S)-2-tert-butoxy-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)propylcarbamate,
(4-(3-(4-((2R)-2-amino-3-(benzyloxy)propanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R,2S)-2-(benzyloxy)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)propylcarbamate,
tert-butyl (1R)-5-((aminocarbonyl)amino)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)pentylcarbamate,
tert-butyl (1R)-4-((aminocarbonyl)amino)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)butylcarbamate,
tert-butyl (1R)-1-benzyl-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-2-oxoethylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-(4-fluorobenzyl)-2-oxoethylcarbamate,
(4-(3-(4-((2R)-2-amino-3-(4-fluorophenyl)propanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(4R)-4-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-2-azetidinone,
(4S)-4-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-2-azetidinone,
tert-butyl (2S)-2-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
cyclopropyl(4-(3-(4-((2S)-pyrrolidinylcarbonyl)-1-piperazinyl)propoxy)phenyl)methanone,
cyclopropyl(4-(3-(4-((2R)-pyrrolidinylacetyl)-1-piperazinyl)propoxy)phenyl)methanone,
(4-(3-(4-((2R)-2-amino-3-(2-thienyl)propanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(4-(3-(4-((2R)-2-amino-3-(1-methyl-1H-imidazol-4-yl)propanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-2-oxo-1-(1,3-thiazol-5-ylmethyl)ethylcarbamate,
1-((1S)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-2-methylpropyl)tetrahydro-2(1H)-pyrimidinone,
tert-butyl (1S)-2-(4-(2-((4-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)ethyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
4xe2x80x2-(2-(4-((2S)-2-aminopropanoyl)-1-piperazinyl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1R)-2-(4-(2-((4-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)ethyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
4xe2x80x2-(2-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
4-(3-(4-(((tert-butoxycarbonyl)(methyl)amino)acetyl)-1-piperazinyl)propoxy)-4-cyano-1,1xe2x80x2-biphenyl
4xe2x80x2-(3-(4-((methylamino)acetyl)-1-piperazinyl)propoxy)( 1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1R)-2-(4-(2-((4-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)ethyl)-1-piperazinyl)-1-methyl-2-oxoethyl(methyl)carbamate,
4xe2x80x2-(2-(4-((2R)-2-(methylamino)propanoyl)-1-piperazinyl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1R)-2-(4-(3-((4xe2x80x2-cyano( 1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
4xe2x80x2-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)( 1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1R)-2-(4-(3-((4-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl(methyl)carbamate,
4xe2x80x2-(3 -(4-((2R)-2-(methylamino)propanoyl)-1-piperazinyl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1S)-2-(4-(3-((4-cyano( 1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (2R)-2-((4-(2-((4-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)ethyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
4xe2x80x2-(2-(4-((2R)-pyrrolidinylcarbonyl)-1-piperazinyl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (2S)-2-((4-(2-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)ethyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
tert-butyl (2R)-2-((4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
4xe2x80x2-(3-(4-(aminoacetyl)-1-piperazinyl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
4-(3-(4-(3-((tert-butoxycarbonyl)amino)propanoyl)-1-piperazinyl)propoxy)-4-cyano-1,1xe2x80x2-biphenyl
4xe2x80x2-(3-(4-(3-aminopropanoyl)-1-piperazinyl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
N-(3 -(4-(3 -((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-3-oxopropyl)-2,2-dimethylpropanamide,
N-(3 -(4-(3 -((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-3-oxopropyl)-3,3-dimethylbutanamide,
N-(3-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-3-oxopropyl)cyclopropanecarboxamide,
N-(3-(4-(3-((4xe2x80x2-cyano( 1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-3-oxopropyl)-4-morpholinecarboxamide,
tert-butyl 3-(4-(3 -(4-(cyclopropylcarbonyl)phenoxy)propyl)-1,4-diazepan-1-yl)-3-oxopropylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethylcarbamate,
(4-(3-(4-((2S)-2-aminopropanoyl)-1,4-diazepan-1-yl)propoxy)phenyl)(cyclopropyl)methanone,
4xe2x80x2-(3-(4-((2R)-2-aminopropanoyl)-1,4-diazepan-1-yl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1S)-2-(4-(3-((4xe2x80x2-cyano( 1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (1R)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1,4-diazepan-1-yl)carbonyl)propylcarbamate,
(4-(3-(4-((2R)-2-aminobutanoyl)-1,4-diazepan-1-yl)propoxy)phenyl)(cyclopropyl)methanone,
4xe2x80x2-(3-(4-((2R)-2-aminobutanoyl)-1,4-diazepan-1-yl)propoxy)( 1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (2S)-2-(2-(4-(3 -(4-(cyclopropylcarbonyl)phenoxy)propyl)-1,4-diazepan-1-yl)-2-oxoethyl)-1-pyrrolidinecarboxylate,
cyclopropyl(4-(3-(4-((2S)-pyrrolidinylacetyl)-1,4-diazepan-1-yl)propoxy)phenyl)methanone,
tert-butyl (2S)-2-(2-(4-(3-((4-cyano( 1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1,4-diazepan-1-yl)-2-oxoethyl)-1-pyrrolidinecarboxylate,
N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-thiophenecarboxamide,
(4-(3-(4-(((1S, 2R)-2-aminocyclopropyl)carbonyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(2R)-N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-pyrrolidinecarboxamide,
(4-(3-(4-((2-aminocyclopentyl)carbonyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(4-(3-(4-((2R)-azetidinylcarbonyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(4-(((3R)-3-(4-((2R)-2-aminobutanoyl)-1-piperazinyl)butyl)oxy)phenyl)(cyclopropyl)methanone,
(4-(((3R)-3-(4-((2R)-2-aminopentanoyl)-1-piperazinyl)butyl)oxy)phenyl)(cyclopropyl)methanone,
tert-butyl 3-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-1-azetidinecarboxylate,
tert-butyl 4-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-4-oxobutylcarbamate,
tert-butyl (1R)-2-(4-((3S)-3-(4-(cyclopropylcarbonyl)phenoxy)-3-phenylpropyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
N-((1R)-2-(4-(3-((4-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1,4-diazepan-1-yl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethyl)-2-furamide,
(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
cyclopropyl(4-(3 -(4-((2R)-2-(isopropylamino)propanoyl)-1-piperazinyl)propoxy)phenyl)methanone,
4xe2x80x2-(2-(4-((2S)-pyrrolidinylcarbonyl)-1-piperazinyl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
N-((1S)-2-(4-(3-(3-fluoro-4-( 1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-ethyl-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3 -fluoro-4-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-propyl-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3 -(3-fluoro-4-(5-isobutyl-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3 -(4-(5-butyl-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3 -fluoro-4-(5-isopentyl-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3 -fluoro-4-(5-neopentyl-1,2,4-oxadiazol-3 -yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-(( 1S)-2-(4-(3 -(4-(5-(1-ethylpropyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(methoxymethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(isopropoxymethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-((2-methoxyethoxy)methyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-tetrahydro-2-furanyl-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-tetrahydro-3-furanyl-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-cyano-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5 -cyclopentyl-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-(cyclohexylmethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-((dimethylamino)methyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-(2-(dimethylamino)ethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(1-pyrrolidinylmethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(2-(1-pyrrolidinyl)ethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(1-piperidinylmethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(2-(1-piperidinyl)ethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(4-morpholinylmethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(2-(4-morpholinyl)ethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-(tert-butoxymethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-(2-tert-butoxyethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
tert-butyl 3-(2-fluoro-4-(3-(4-((2S)-2-(2-furoylamino)propanoyl)-1,4-diazepan-1-yl)propoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate,
tert-butyl (3-(2-fluoro-4-(3-(4-((2S)-2-(2-furoylamino)propanoyl)-1,4-diazepan-1-yl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)acetate,
N-((1S)-2-(4-(3-(4-(5 -((1S)-1-aminoethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-((1S)-1-amino-2-methylpropyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-((1S)-1-amino-3-methylbutyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-((2S)-pyrrolidinyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-((1S)-1-amino-2-phenylethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-((1S)-1-amino-2-(1H-indol-3-yl)ethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-((1S)-1-amino-2-hydroxyethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-((1S)-1-amino-2-(4-hydroxyphenyl)ethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-((1R)-1-aminoethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-((1R)-1-amino-2-phenylethyl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(2-furyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(3-furyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(2-thienyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(3-thienyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(1H-pyrrol-3-yl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(1,3-oxazol-4-yl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(1,3 -thiazol-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(1H-imidazol-4-yl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(5-isoxazolyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2 -(4-(3-(3-fluoro-4-(5 -(2-pyridinyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(2-pyridinylmethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5 -(3-pyridinyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(3-pyridinylmethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(4-pyridinyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(4-pyridinylmethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(4-pyridazinyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-l-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(4-pyrimidinyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(2-pyrazinyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-benzyl-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-benzyl-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(2-phenylethyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(6-quinolinyl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-(1,3-benzothiazol-6-yl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5-(1,3-benzoxazol-4-yl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(4-(5 -(1H-benzimidazol-6-yl)-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1S)-2-(4-(3-(3-fluoro-4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
tert-butyl 3-(3-(4-acetylphenoxy)propyl)-3,8-diazabicyclo(3.2.1 )octane-8-carboxylate,
tert-butyl 3-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-3,8-diazabicyclo(3.2.1)octane-8-carboxylate,
tert-butyl (1R)-2-(3-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-3,8-diazabicyclo(3.2.1)oct-8-yl)-1-methyl-2-oxoethylcarbamate,
(4-(3-(8-((2R)-2-aminopropanoyl)-3,8-diazabicyclo(3.2.1)oct-3-yl)propoxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1S, 4S)-5-(3-(4-acetylphenoxy)propyl)-2,5-diazabicyclo(2.2.1)heptane-2-carboxylate,
tert-butyl (1R, 4R)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-2,5-diazabicyclo(2.2.1)heptane-2-carboxylate,
tert-butyl (1S, 4S)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-2,5-diazabicyclo(2.2.1)heptane-2-carboxylate,
cyclopropyl(4-(3-((1R, 4R)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
cyclopropyl(4-(3-((1S, 4S)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
cyclopropyl(4-(3-((1S,4S)-5-(cyclopropylcarbonyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
4xe2x80x2-(2-((1R, 4R)-5-((4-methylphenyl)sulfonyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
4xe2x80x2-(3-((1R, 4R)-5 -((4-methylphenyl)sulfonyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1R)-2-((1R, 4R)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)-1-methyl-2-oxoethylcarbamate,
(4-(3-((1R, 4R)-5-((2R)-2-aminopropanoyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R)-2-((1S, 4S)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (1S)-2-((1S, 4S)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)-1-methyl-2-oxoethylcarbamate,
tert-butyl 3-((1S, 4S)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)-3-oxopropylcarbamate,
cyclopropyl(4-(3-((1S, 4S)-5-(ethylsulfonyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
cyclopropyl(4-(3-((1S, 4S)-5-(4-morpholinylcarbonyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
(1S, 4S)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-N,N-dimethyl-2,5-diazabicyclo(2.2.1)heptane-2-sulfonamide,
cyclopentyl (1S, 4S)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-2,5-diazabicyclo(2.2.1)heptane-2-carboxylate,
(1S, 4S)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-N,N-dimethyl-2,5-diazabicyclo(2.2.1)heptane-2-carboxamide,
ethyl (1S, 4S)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-2,5-diazabicyclo(2.2.1)heptane-2-carboxylate,
(4-(3-((1S, 4S)-5-(cyclobutylcarbonyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)(cyclopropyl)methanone,
cyclopropyl(4-(3-((1S, 4S)-5-(3,3-dimethylbutanoyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
(4-(3-((1S, 4S)-5-(cyclohexylcarbonyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)(cyclopropyl)methanone,
cyclopropyl(4-(3-((1S, 4S)-5-(4-fluorobenzoyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
cyclopropyl(4-(3-((1S, 4S)-5-(2-thienylcarbonyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
cyclopropyl(4-(3-((1S, 4S)-5-(2-furoyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
(4-(3-((1S, 4S)-5-benzoyl-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)(cyclopropyl)methanone,
(1S, 4S)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-N-methyl-N-phenyl-2,5-diazabicyclo(2.2.1)heptane-2-carboxamide,
cyclopropyl(4-(3-((1S, 4S)-5-(phenylsulfonyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
4-fluorophenyl (1S, 4S)-5-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-2,5-diazabicyclo(2.2.1)heptane-2-carboxylate,
cyclopropyl(4-(3-((1S, 4S)-5-(2-pyridinylcarbonyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)methanone,
(4-(3-((1S, 4S)-5-((2R)-2-aminopropanoyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)(cyclopropyl)methanone, and
(4-(3-((1S,4S)-5-(3-aminopropanoyl)-2,5-diazabicyclo(2.2.1)hept-2-yl)propoxy)phenyl)(cyclopropyl)methanone.
4xe2x80x2-(4-(1,4-diazepan-1-yl)-1-butynyl)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
N-((1R)-2-(4-(4-(4-(cyclopropylcarbonyl)phenyl)-3-butynyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1R)-2-(4-(4-(4-cyano(1,1xe2x80x2-biphenyl)-4-yl)-3-butynyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl)-2-furamide,
tert-butyl 4-(4-(4-cyano(1,1xe2x80x2-biphenyl)-4-yl)-3-butynyl)-1,4-diazepane-1-carboxylate,
tert-butyl 4-(4-(4-(cyclopropylcarbonyl)phenyl)-3-butynyl)-1-piperazinecarboxylate hydrochloride,
Preferred compounds of the instant invention include
(4-(3-(4-((2S)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(2S)-1-(4-(3-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy)propyl)-1-piperazinyl)-1-oxo-2-propanamine,
tert-butyl 2-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-2-oxoethylcarbamate,
2-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-2-oxoethanamine,
tert-butyl 3-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-3-oxopropylcarbamate,
3-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-3-oxo-1-propanamine,
tert-butyl (1R)-2-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
(2R)-1-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-1-oxo-2-propanamine,
tert-butyl (1S)-2-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
(2S)-1-(4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)-1-oxo-2-propanamine,
tert-butyl (2S)-2-((4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
4-bromophenyl 3-(4-((2S)-pyrrolidinylcarbonyl)-1-piperazinyl)propyl ether
tert-butyl (2R)-2-((4-(3-(4-bromophenoxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
4-bromophenyl 3-(4-((2R)-pyrrolidinylcarbonyl)-1-piperazinyl)propyl ether
tert-butyl (1R)-1-methyl-2-oxo-2-(4-(3-(4-(trifluoromethyl)phenoxy)propyl)-piperazinyl)ethylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-cyanophenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl 3-(4-(3-(4-cyano-3-fluorophenoxy)propyl)-1-piperazinyl)-3-oxopropylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-(aminocarbonyl)-3-fluorophenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
1-(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)ethanone,
N-((1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)acetamide,
ethyl (1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
N-((1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)cyclopropanecarboxamide,
tert-butyl (1R)-2-(4-((1R)-3-(4-acetylphenoxy)-1-methylpropyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (1S)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (2R)-2-((4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
tert-butyl (2S)-2-((4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
N-((1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)methanesulfonamide,
N-((1R)-2-(4-(3-(4-acetylphenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-N,N-dimethylsulfamide,
1-(4-(3-(4-((methylamino)acetyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl 2-(4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)-2-oxoethylcarbamate,
1-(4-(3-(4-(3-aminopropanoyl)-1piperazinyl)propoxy)phenyl)-1-hexanone,
1-(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1S)-1-((4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)carbonyl)-2-methylpropylcarbamate,
1-(4-(3-(4-((2S)-2-amino-3-methylbutanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1R)-1-((4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)carbonyl)-2-methylpropylcarbamate,
1-(4-(3-(4-((2R)-2-amino-3-methylbutanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1S)-1-((4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)carbonyl)-3-methylbutylcarbamate,
1-(4-(3-(4-((2S)-2-amino-4-methylpentanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1R)-1-((4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)carbonyl)-3-methylbutylcarbamate,
1-(4-(3-(4-((2R)-2-amino-4-methylpentanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1S)-1-((benzyloxy)methyl)-2-(4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)-2-oxoethylcarbamate,
1-(4-(3-(4-((2R)-2-amino-3-hydroxypropanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
1-(4-(3-(4-((2S)-2-amino-3-(benzyloxy)propanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1S)-2-(4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)-2-oxo-1-(4-pyridinylmethyl)ethylcarbamate,
1-(4-(3-(4-((2S)-2-amino-3-(4-pyridinyl)propanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1R)-2-(4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)-2-oxo-1-(4-pyridinylmethyl)ethylcarbamate,
1-(4-(3-(4-((2R)-2-amino-3-(4-pyridinyl)propanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
tert-butyl (1S)-2-(4-(3-(4-hexanoylphenoxy)propyl)-1-piperazinyl)-1-(1H-imidazol-4-ylmethyl)-2-oxoethylcarbamate,
1-(4-(3-(4-((2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl)-1-piperazinyl)propoxy)phenyl)-1-hexanone,
(4-(((3R)-3-(4-(3-aminopropanoyl)-1-piperazinyl)butyl)oxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R)-2-(4-((1R)-3-(4-(cyclopropylcarbonyl)phenoxy)-1-methylpropyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
(4-(((3R)-3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)butyl)oxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R)-2-(4-((1S)-3-(4-(cyclopropylcarbonyl)phenoxy)-1-methylpropyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
cyclopropyl(4-(((3R)-3-(4-((methylamino)acetyl)-1-piperazinyl)butyl)oxy)phenyl)methanone,
(4-(3-(4-((2R)-2-amino-3,3-dimethylbutanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-3,3-dimethylbutylcarbamate,
tert-butyl (1R)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-3,3-dimethylbutylcarbamate,
(4-(3-(4-((2R)-2-aminobutanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
cyclopropyl(4-(3-(4-((2R)-2-(methylamino)-3-phenylpropanoyl)-1-piperazinyl)propoxy)phenyl)methanone,
(4-(3-(4-((2R,3S)-2-amino-3-hydroxybutanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
benzyl (1R)-1-(tert-butoxymethyl)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-2-oxoethylcarbamate,
(4-(3-(4-((2R)-2-amino-3-tert-butoxypropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R,2S)-2-tert-butoxy-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)propylcarbamate,
(4-(3-(4-((2R)-2-amino-3-(benzyloxy)propanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R,2S)-2-(benzyloxy)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)propylcarbamate,
tert-butyl (1R)-5-((aminocarbonyl)amino)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)pentylcarbamate,
tert-butyl (1R)-4-((aminocarbonyl)amino)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)butylcarbamate,
tert-butyl (1R)-1-benzyl-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-2-oxoethylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-(4-fluorobenzyl)-2-oxoethylcarbamate,
(4-(3-(4-((2R)-2-amino-3-(4-fluorophenyl)propanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(4R)-4-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-2-azetidinone,
(4S)-4-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-2-azetidinone,
tert-butyl (2S)-2-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
cyclopropyl(4-(3.-(4-((2)-pyrrolidinylcarbonyl)-1-piperazinyl)propoxy)phenyl)methanone,
cyclopropyl(4-(3-(4-((2R)-pyrrolidinylacetyl)-1-piperazinyl)propoxy)phenyl)methanone,
(4-(3-(4-((2R)-2-amino-3-(2-thienyl)propanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(4-(3-(4-((2R)-2-amino-3-(1-methyl-1H-imidazol-4-yl)propanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
tert-butyl (1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-2-oxo-1-(1,3-thiazol-5-ylmethyl)ethylcarbamate,
1-((1S)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-2-methylpropyl)tetrahydro-2(1H)-pyrimidinone,
tert-butyl (1S)-2-(4-(2-((4-cyano(1,1 -biphenyl)-4-yl)oxy)ethyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
4xe2x80x2-(2-(4-((2S)-2-aminopropanoyl)-1-piperazinyl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1R)-2-(4-(2-((4-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)ethyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
4xe2x80x2-(2-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
4-(3-(4-(((tert-butoxycarbonyl)(methyl)amino)acetyl)-1-piperazinyl)propoxy)-4-cyano-1,1xe2x80x2-biphenyl
4xe2x80x2-(3-(4-((methylamino)acetyl)-1-piperazinyl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1R)-2-(4-(2-((4xe2x80x2-cyano(1,1 -biphenyl)-4-yl)oxy)ethyl)-1-piperazinyl)-1-methyl-2-oxoethyl(methyl)carbamate,
4xe2x80x2-(2-(4-((2R)-2-(methylamino)propanoyl)-1-piperazinyl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1R)-2-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
4xe2x80x2-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1R)-2-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl(methyl)carbamate,
4xe2x80x2-(3-(4-((2R)-2-(methylamino)propanoyl)-1-piperazinyl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1S)-2-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (2R)-2-((4-(2-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)ethyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
4xe2x80x2-(2-(4-((2R)-pyrrolidinylcarbonyl)-1-piperazinyl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (2S)-2-((4-(2-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)ethyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
tert-butyl (2R)-2-((4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)carbonyl)-1-pyrrolidinecarboxylate,
4xe2x80x2-(3-(4-(aminoacetyl)-1-piperazinyl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
4-(3-(4-(3-((tert-butoxycarbonyl)amino)propanoyl)-1-piperazinyl)propoxy)-4xe2x80x2-cyano-1,1xe2x80x2-biphenyl
4xe2x80x2-(3-(4-(3-aminopropanoyl)-1-piperazinyl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
N-(3-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-3-oxopropyl)-2,2-dimethylpropanamide,
N-(3-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-3-oxopropyl)-3,3-dimethylbutanamide,
N-(3-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-3-oxopropyl)cyclopropanecarboxamide,
N-(3-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1-piperazinyl)-3-oxopropyl)-4-morpholinecarboxamide,
tert-butyl 3-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1,4-diazepan-1-yl)-3-oxopropylcarbamate,
tert-butyl (1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethylcarbamate,
(4-(3-(4-((2S)-2-aminopropanoyl)-1,4-diazepan-1-yl)propoxy)phenyl)(cyclopropyl)methanone,
4xe2x80x2-(3-(4-((2R)-2-aminopropanoyl)-1,4-diazepan-1-yl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (1S)-2-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1,4-diazepan-1-yl)-1-methyl-2-oxoethylcarbamate,
tert-butyl (1R)-1-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1,4-diazepan-1-yl)carbonyl)propylcarbamate,
(4-(3-(4-((2R)-2-aminobutanoyl)-1,4-diazepan-1-yl)propoxy)phenyl)(cyclopropyl)methanone,
4xe2x80x2-(3-(4-((2R)-2-aminobutanoyl)-1,4-diazepan-1-yl)propoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile,
tert-butyl (2S)-2-(2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1,4-diazepan-1-yl)-2-oxoethyl)-1-pyrrolidinecarboxylate,
cyclopropyl(4-(3-(4-((2S)-pyrrolidinylacetyl)-1,4-diazepan-1-yl)propoxy)phenyl)methanone,
tert-butyl (2S)-2-(2-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1,4-diazepan-1-yl)-2-oxoethyl)-1-pyrrolidinecarboxylate,
N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide,
N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-thiophenecarboxamide,
(4-(3-(4-(((1S,2R)-2-aminocyclopropyl)carbonyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(2R)-N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-pyrrolidinecarboxamide,
(4-(3-(4-((2-aminocyclopentyl)carbonyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(4-(3-(4-((2R)-azetidinylcarbonyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
(4-(((3R)-3-(4-((2R)-2-aminobutanoyl)-1-piperazinyl)butyl)oxy)phenyl)(cyclopropyl)methanone,
(4-(((3R)-3-(4-((2R)-2-aminopentanoyl)-1-piperazinyl)butyl)oxy)phenyl)(cyclopropyl)methanone,
tert-butyl 3-((4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)carbonyl)-1-azetidinecarboxylate,
tert-butyl 4-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-4-oxobutylcarbamate,
tert-butyl (1R)-2-(4-((3S)-3-(4-(cyclopropylcarbonyl)phenoxy)-3-phenylpropyl)-1-piperazinyl)-1-methyl-2-oxoethylcarbamate,
N-((1R)-2-(4-(3-((4xe2x80x2-cyano(1,1xe2x80x2-biphenyl)-4-yl)oxy)propyl)-1,4-diazepan-1-yl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethyl)-2-furamide,
(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone,
cyclopropyl(4-(3-(4-((2R)-2-(isopropylamino)propanoyl)-1-piperazinyl)propoxy)phenyl)methanone,
4xe2x80x2-(2-(4-((2S)-pyrrolidinylcarbonyl)-1-piperazinyl)ethoxy)(1,1xe2x80x2-biphenyl)-4-carbonitrile;
N-[(1R)-2-(4-{3-[3-fluoro-4-(5-propyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl]-2-furamide,
N-[(1R)-2-(4-{3-[3-fluoro-4-(5-isopentyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl]-2-furamide,
N-{(1R)-2-[4-(3-{3-fluoro-4-[5-(isopropoxymethyl)-1,2,4-oxadiazol-3-yl]phenoxy}propyl)-1,4-diazepan-1-yl]-1-methyl-2-oxoethyl}-2-furamide,
N-[(1R)-2-(4-{3-[4-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-3-fluorophenoxy]propyl}-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl]-2-furamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1,4-diazepan-1-yl]-1-methyl-2-oxoethyl}-2-furamide,
tert-butyl (1S)-1-{3-[2-fluoro-4-(3-{4-[(2R)-2-(2-furoylamino)propanoyl]-1,4-diazepan-1-yl}propoxy)phenyl]-1,2,4-oxadiazol-5-yl}ethylcarbamate,
N-{(1R)-2-[4-(3-{3-fluoro-4-[5-(3-furyl)-1,2,4-oxadiazol-3-yl]phenoxy}propyl)-1,4-diazepan-1-yl]-1-methyl-2-oxoethyl}-2-furamide,
N-{(1R)-2-[4-(3-{3-fluoro-4-[5-(2-thienyl)-1,2,4-oxadiazol-3-yl]phenoxy}propyl)-1,4-diazepan-1-yl]-1-methyl-2-oxoethyl}-2-furamide,
N-{(1R)-2-[4-(3-{3-fluoro-4-[5-(1,3-thiazol-2-yl)-1,2,4-oxadiazol-3-yl]phenoxy}propyl)-1,4-diazepan-1-yl]-1-methyl-2-oxoethyl}-2-furamide,
N-{(1R)-2-[4-(3-{3-fluoro-4-[5-(4-pyridinyl)-1,2,4-oxadiazol-3-yl]phenoxy}propyl)-1,4-diazepan-1-yl]-1-methyl-2-oxoethyl}-2-furamide,
N-[(1R)-2-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1,4-diazepan-1-yl)-1-methyl-2-oxoethyl]-2-furamide,
N-{(1R)-2-[4-(3-{3-fluoro-4-[5-(2-phenylethyl)-1,2,4-oxadiazol-3-yl]phenoxy}propyl)-1,4-diazepan-1-yl]-1-methyl-2-oxoethyl}-2-furamide,
4xe2x80x2-cyano-N-[3-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-3-oxopropyl]benzamide,
N-[3-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-3-oxopropyl]-3-thiophenecarboxamide,
(2R)-N-[3-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-3-oxopropyl]tetrahydro-2-furancarboxamide,
N-[3-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-3-oxopropyl]-3,5-dimethyl-2-thiophenecarboxamide,
N-[3-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-3-oxopropyl]-2,5-dimethyl-3-furamide,
N-[3-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-3-oxopropyl]cyclopropanecarboxamide,
N-[(1R)-2-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]-2-thiophenecarboxamide,
N-[(1R)-2-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]nicotinamide,
N-[(1R)-2-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]-2-furamide,
N-[(1R)-2-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]-5-isoxazolecarboxamide,
(2S)-N-[(1R)-2-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]tetrahydro-2-furancarboxamide,
N-[(1R)-2-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]-3-(4-morpholinyl)propanamide,
N-[(1R)-2-(4-{3-[3-fluoro-4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]-3-methylbutanamide,
(2R)-1-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-oxo-2-propanamine,
(2R)-1-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1,4-diazepan-1-yl]-1-oxo-2-propanamine,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}propanamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-3,3-dimethylbutanamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-3-(4-morpbolinyl)propanamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl] -1-methyl-2-oxoethyl}-4-methylbenzamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-4-fluorobenzamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-4-methoxybenzamide,
3,4-dichloro-N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}benzamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1,4-diazepan-1-yl]-1-methyl-2-oxoethyl}-2-methylpropanamide,
4-chloro-N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl] -3-fluorophenoxy}propyl)-1,4-diazepan-1-yl]-1-methyl-2-oxoethyl}benzamide,
4xe2x80x2-cyano-N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1,4-diazepan-1-yl]-1-methyl-2-oxoethyl}benzamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl] -1-methyl-2-oxoethyl}-4-(dimethylamino)benzamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-piperazinyl]-1-methyl-2-oxoethyl}nicotinamide,
2-chloro-N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}benzamide,
N-{(1R)-2-[4-(3-{4-[5 -(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-1,3-benzodioxole-5-carboxamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-4-isopropoxybenzamide,
N-{(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl] -3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-3-fluoro-4-methoxybenzamide,
4-[({(1R)-2-[4-(3-{4-[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}amino)carbonyl]benzoic acid,
N-{(1R)-2-[4-(3-{3-fluoro-4-[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]phenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-2-thiophenecarboxamide,
N-{(1R)-2-[4-(3-{4-[5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-2-thiophenecarboxamide,
N-{(1R)-2-[4-(3-{4-[5-(3,5-dichlorophenyl)-1,2,4-oxadiazol-3-yl]-3-fluorophenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-2-thiophenecarboxamide,
N-((1R)-2-{4-[3-(3-fluoro-4-{5-[3-oxo-3-(1-pyrrolidinyl)propyl]-1,2,4-oxadiazol-3-yl}phenoxy)propyl]-1-piperazinyl}-1-methyl-2-oxoethyl)-2-thiophenecarboxamide,
ethyl 3-{2-fluoro-4-[3-(4-{(2R)-2-[(2-thienylcarbonyl)amino]propanoyl}-1-piperazinyl)propoxy]phenyl}-1,2,4-oxadiazole-5-carboxylate,
N-[(1R)-2-(4-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]-2-methylbenzamide,
N-[(1R)-2-(4-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]-3-methoxybenzamide,
4-bromo-N-[(1R)-2-(4-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]benzamide,
N-[(1R)-2-(4-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]-4-phenoxybenzamide,
N-[(1R)-2-(4-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]-3,5-dimethylbenzamide,
N-[(1R)-2-(4-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethyl]-2,5-dimethoxybenzamide, and
N-{(1R)-2-[4-(3-{3-fluoro-4-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]phenoxy}propyl)-1-piperazinyl]-1-methyl-2-oxoethyl}-2-thiophenecarboxamide.
Determination of Biological Activity
H3 Receptor Binding
To determine the effectiveness of representative compounds of this invention as H3 receptor ligands, the following tests were conducted according to methods previously described ((European Journal of pharmacology, 188:219-227 (1990); Journal of Pharmacology and Experimental Therapeutics, 275: 598-604 (1995); Journal of Pharmacology and Experimental Therapeutics, 276:1009-1015 (1996); Biochemical Pharmacology, 22: 3099-3108 (1973)).
Briefly, male Sprague-Dawley rat brain cortices were homogenized (1 g tissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA containing protease inhibitor cocktail (Calbiochem) using a polytron set at 20,500 rpm. Homogenates were centrifuged for 20 minutes at 40,000xc3x97g. The supernatant was decanted, and pellets were weighed. The pellet was resuspended by polytron homogenization in 40 mL 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and centrifuged for 20 minutes at 40,000xc3x97g. The membrane pellet was resuspended in 6.25 volumes (per gram wet weight of pellet) of 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and aliquots flash frozen in liquid N2 and stored at xe2x88x9270xc2x0 C. until used in assays. Rat cortical membranes (12 mg wet weight/tube) were incubated with (3H)-N-xcex1-methylhistamine (xe2x88x920.6 nM) with or without H3xe2x80x94HR antagonists in a total incubation volume of 0.5 mL of 50 mM Tris-HCl/5 mM EDTA (pH 7.7). Test compounds were added to the incubation mixtures prior to initiating the incubation assay by addition of the membranes. Thioperamide (3 xcexcM) was used to determine nonspecific binding. Binding incubations were conducted for 30 minutes at 25xc2x0 C. and terminated by addition of 2 mL of ice cold 50 mM Tris-HCl (H 7.7) and filtration through 0.3% polyethylenimine-soaked Unifilter plates (Packard). These filters were washed 4 additional times with 2 mL of ice-cold 50 mM Tris-HCl and dried for 1 hour. Radioactivity was determined using liquid scintillation counting techniques. Results were analyzed by Hill transformation and Ki values were determined using the Cheng-Prusoff equation. The data in Table 1Data represent the geometric mean values of 2-10 separate experiments.
Abbreviations
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are DMA for dimethylacetamide; HPLC for high pressure liquid chromatography; HOBt for 1-hydroxybenzotriazole; THF for tetrahydrofuran; Ac for acetate; MeCN for acetonitrile; MeOH for methanol; TMSCl for trimethylsilyl chloride; TMSBr for trimethylsilylbromide; TEA for triethylamine; DBU for 1,8-diazabicyclo(5.4.0)undec-7-ene; DMF for N,N-dimethyl formamide; DCM for dichloromethane, DMSO for dimethyl sulfoxide; Me for methyl; Et for ethyl; ixe2x80x94Pr for isopropyl; Ph for phenyl; TBME for tertiary-butyl methyl ether; PhOPh for diphenyl ether; LDA for lithium diisopropylamide; rpm for rotations per minute; g for gravity; NMP for N-methylpyrrolidine; EtOH for ethanol; EtOAc for ethyl acetate; DMAP for N,N-dimethylaminopyridine; HMPA for hexamethylphosphoramide; NCS for N-chlorosuccinimide, NBS for N-bromosuccinimide; BOPCl for bis(2-oxo-3-oxazolidinyl)phosphinic chloride; TFA for trifluoroacetic acid; DCC for 1,3-dicyclohexylcarbodiimide; CDI for 1,1-Carbonyldiimidazole; HATU for O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate; EDCI for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; PyBOP for benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate; TsOH for para-toluenesulfonic acid; DEAD for diethyl azodicarboxylate; DAID for diisopropyl azodicarboxylate; TBDMSCI for tertiary-butyldimethylsilyl chloride; Boc for tertiary-butoxycarbonyl; AcOH for acetic acid; DPPE for bis(diphenylphosphino)ethane.
Synthetic Methods
The compounds and processes of this invention will be better understood in connection with the following synthetic schemes which illustrate methods by which the compounds of this invention can be prepared. The compounds of this invention can be prepared by a variety of procedures. Representative procedures are shown in Schemes 1-5. The groups L1, L2, Q1, Q2, n, R5, R6, R7 and R8 are as defined above.
It will be readily apparent that other compounds of this invention can by synthesized by the substitution of appropriate starting materials and reagents in the syntheses shown below. It will also be apparent that protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, to successfully complete the syntheses of compounds of this invention. Starting materials and reagents are available commercially or can be prepared synthetically by known methods well-known in the art. In particular, optionally substituted 1,4-piperazines; optionally substituted 1,4-diazepanes; and (1S,4S)-(+)-2,5-diazabicyclo(2.2.1)heptane are commercially available. (1R,4R)-(xe2x88x92)-2,5-diazabicyclo(2.2.1)heptane was prepared according to the procedure described in J. Med. Chem. 1990, 33, 1344. The preparation of 3,8-diazabicyclo(3.2.1)octane is described below.
All of the reactions discussed in the schemes are run in solvents in which the starting materials and products are not reactive, unless otherwise specified, and in which the starting materials are at least partially soluble. The appropriate solvent for each reaction will be apparent to one skilled in the art. 
As shown in Scheme 1, compound (i) can be converted to compound (ii) by treating the former with a reducing agent in a solvent. 3,8-diazabicyclo(3.2.1)octane, compound (i), was prepared according to the procedure described in Tetrahedron 1992, 48, 4985. Specific examples of reducing agents include LiAlH4, BH3-THF, and NaAlH2(OCH2CH2OCH3)2. Specific examples of solvents include THF, diethyl ether, and glyme. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 2 hours to about 24 hours and can be selected depending on the reaction temperature. 
As shown in Scheme 2, the conversion of compounds of formula (iii) and (iv) to (v) can be accomplished by combining (iii) and (iv) with a base in a solvent. Specific examples of (iii) include cyclopropyl para-hydroxyphenyl ketone, 4-hydroxybenzonitrile, 4-bromophenol, 4xe2x80x2-cyano-4xe2x80x2-hydroxybiphenyl, 4-hydroxyacetophenone, 2-(4xe2x80x2-hydroxyphenyl)pyridine, 4xe2x80x2-cyano-3-fluorophenol, 4-trifluoromethylphenol, and 4-hydroxy-phenyl-1-hexanone. Specific examples of (iv), wherein X1 and X2 are the same or different halides, include 1-bromo-2-chloroethane; 1-bromo-3-chloropropane; 1-bromo-4-chlorobutane; 1,2-dibromoethane; 1,3-dibromopropane; 1,4-dibromobutane; 1-chloro-3-phenyl propanol; 1,3-butanediol. Specific examples of bases include K2CO3, Cs2CO3, NaHCO3, LiOH, NaOH, KOH, pyridine, lutidine, TEA, DBU and diisopropylethylamine. Specific examples of solvents include 2-butanone, THF, DMF, NMP, acetone, benzene, toluene, DCM and chloroform. Although the reaction generally proceeds at about 70-80xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 6 hours to about 36 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (iii) and (iv) in 2-butanone were treated with K2CO3 and refluxed for about 24 hours.
Alternatively, compounds of formula (iii) and (iv) can be combined to form compounds of formula (v) by treating the (iv) with a hydroxyl activating group precursor and a nucleophile. Specific examples of hydroxyl activating groups include trifluoroacetic anhydride, diazo compounds and phosphines, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of diazo compounds include DEAD, and DIAD. Specific examples of phosphines include PPh3, PEt3, DPPE and PMe3. Specific examples of nucleophiles include carboxylate anions, phenol anions, thiol anions and alkoxide anions. More preferred are the oxygen anions of cyclopropyl para-hydroxyphenyl ketone, cyclopropyl para-hydroxyphenyl ketone, 4-hydroxybenzonitrile, 4-bromophenol, 4xe2x80x2-cyano-4xe2x80x2-hydroxybiphenyl, 4-hydroxyacetophenone, 2-(4xe2x80x2-hydroxyphenyl)pyridine, 4xe2x80x2-cyano-3-fluorophenol, 4-trifluoromethylphenol, and 4-hydroxy-phenyl-1-hexanone. Specific examples of solvents include DCM; chloroform; CCl4; THF; and 1,1,1-trichloroethane. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about one hour to about 16 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (iv) and the oxygen anion of para-hydroxy-4-chlorobutyrophenone in about 0xc2x0 C. DCM is treated with DEAD and PPh3, warmed to room temperature and stirred for about 16 hours. 
As shown in Scheme 3, the conversion of (vi) and (v) to (vii) can be achieved by combining (vi) and (v) in the presence of a base, and an optionally added additive, in a solvent. R1, R2, and R3 are defined as in formula (I) and are substituents on the piperazine or diazepane ring. R4 is synonymous with R5 in this scheme and is defined in formula (I). Specific examples of (vi) include diamines such as piperazine, trans-1,4-diaminocyclohexane, 2-methylpiperazine, 2,6-dimethylpiperazine, trans-2,5-dimethylpiperazine, diazepane, and N,Nxe2x80x2-dimethyl-1,3-propanediamine. Specific examples of bases include K2CO3, Na2CO3, NaHCO3, K3PO4, LiOH, NaOH, and KOH. Specific examples of additives include KI, I2, and HI. Specific examples of solvents include acetone, 2-butanone, THF, DCM, and chloroform. Although the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperatures as needed. The reaction time is generally about 12 hours to about five days and can be selected depending on the reaction temperature.
If the diamine used above is protected, it can be deprotected by treating the coupled product with a deprotecting agent in a solvent. Specific examples of deprotecting agents include TBAF, HF, H2 and Pd on carbon, H2 and Pt on carbon, HCl in methanol, Li/NH3, BBr3, TsOH, AcOH and heat, ZnBr2, HgCl2, K2CO3, Zn, and TFA. Specific examples of solvents include diethyl ether, EtOAc, AcOH, isopropyl acetate, methanol, ethanol, DCM, chloroform, acetonitrile, water, THF and mixtures thereof. Although the reaction usually proceeds at room temperature, it may be run at higher or lower temperatures, as needed. The reaction time is generally about one hour to about 24 hours and can be selected depending on the reaction temperature. The deprotecting agent, solvent, temperature, and time are determined by the nature of the protecting group.
The free amine thus formed can then be treated with an acid or an acid derivative, a base and an additive in a solvent. Specific examples of acids or acid derivatives include amino acids, sulfonic acid chlorides, acid anhydrides, acid chlorides, and carboxylic acids. More preferred are the following acids: Nxe2x80x94Bocxe2x80x94(L)xe2x80x94alanine; Nxe2x80x94Bocxe2x80x94glycine; Nxe2x80x94Boc-4-amino-butyric acid; Nxe2x80x94Bocxe2x80x94betaxe2x80x94alanine; Nxe2x80x94Bocxe2x80x94(D)xe2x80x94alanine; Nxe2x80x94Bocxe2x80x94(L)xe2x80x94proline; Nxe2x80x94Bocxe2x80x94(D)xe2x80x94proline; Nxe2x80x94Bocxe2x80x94sarcosine; Nxe2x80x94Bocxe2x80x94(L)xe2x80x94valine; Nxe2x80x94Bocxe2x80x94(D)xe2x80x94valine; Nxe2x80x94Bocxe2x80x94(L)xe2x80x94leucine; Nxe2x80x94Bocxe2x80x94(D)xe2x80x94leucine; Nxe2x80x94Bocxe2x80x94Oxe2x80x94benzylxe2x80x94(L)xe2x80x94serine; Nxe2x80x94Bocxe2x80x94Oxe2x80x94benzylxe2x80x94(D)xe2x80x94serine; Nxe2x80x94Bocxe2x80x94(S)xe2x80x94pyridyl-phenylalanine; Nxe2x80x94Bocxe2x80x94(R)xe2x80x94pyridyl-phenylalanine; Nxe2x80x94Bocxe2x80x94(L)xe2x80x94histidine; Nxe2x80x94Boc-(2R)-2-amino-3,3-dimethylbutanoic acid; Nxe2x80x94Boc-(2R)-2-amino-4,4-dimethylpentanoic acid; Nxe2x80x94Boc-(2R)-2-amino-butanoic acid; Nxe2x80x94Bocxe2x80x94(L)xe2x80x94N-methylphenyl alanine; Nxe2x80x94Bocxe2x80x94(D)xe2x80x94threonine; Nxe2x80x94CBzxe2x80x94(D)xe2x80x94Oxe2x80x94tert-butyl-serine; Nxe2x80x94Bocxe2x80x94(D)xe2x80x94O-tert-butyl-threonine; Nxe2x80x94Bocxe2x80x94(D)xe2x80x94O-benzyl-threonine; Nxe2x80x94Bocxe2x80x94(D)xe2x80x942,6-diamino-carbonyl hexanoic acid; Nxe2x80x94Bocxe2x80x94(D)xe2x80x94phenylalanine; Nxe2x80x94Bocxe2x80x94(D)xe2x80x944-fluoro-phenylalanine; Nxe2x80x94Bocxe2x80x94(D)xe2x80x944-fluoro-N-methyl-phenylalanine; (2R)-2-azetidinone-4-carboxylic acid; (2S)-2-azetidinone-4-carboxylic acid; Nxe2x80x94Boc-(2R)-2-pyrrolidine acetic acid; Nxe2x80x94Boc-(2R)-2-amino-3-(2)-thiophenyl propanoic acid; Nxe2x80x94Bocxe2x80x94(D)xe2x80x94N-methyl histidine; Nxe2x80x94Boc-(2R)-2-amino-3-(2)-thiazolpropanoic acid; (2S)-3-methyl-2-(2-oxotetrahydro-1(2H)-pyrimidinyl)butanoic acid; Nxe2x80x94Bocxe2x80x94(D)xe2x80x94N-methylalanine; Nxe2x80x94Boc-(2R)-2-aminobutanoic acid; Nxe2x80x94Boc-(2S)-2-pyrrolidino-3-propionic acid; 2,3-methano-3-Nxe2x80x94Boc-amino propionic acid; cis Nxe2x80x94Boc-2-aminocyclopentane; Nxe2x80x94Boc-2-azetidine carboxylic acid; Nxe2x80x94Boc-(2R)-2-aminopropionic acid; Nxe2x80x94Boc-(2R)-2-aminobutyric acid; Nxe2x80x94Boc-3-azetidine carboxylic acid; and Nxe2x80x94Boc-4-aminobutyric acid. Specific examples of bases include TEA; diisopropylethylamine; pyridine; lutidine; DBU, 2,6-di-tertiary-butylpyridine; and imidazole. Specific examples of additives include DMAP, EDCI, BOPCI, DCC, CDI, HATU, PyBOP and combinations thereof. Specific examples of solvents include DCM, chloroform, THF, dioxane, diethyl ether, DMF, NMP and acetonitrile. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about four hours to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the free amine, an N-protected amino acid, diisopropylethylamine, and DMAP in about 0xc2x0 C. DCM were treated with EDCI, warmed to room temperature and stirred for about 16 hours.
The N-protected amine in the coupled product can be can be deprotected by treating it with a deprotecting agent in a solvent. Specific examples of deprotecting agents include H2 and Pd on carbon, H2 and Pt on carbon, HCl in methanol, and TFA. Specific examples of solvents include EtOAc, isopropyl acetate, methanol, ethanol, DCM, and THF. Although the reaction usually proceeds at room temperature, it may be run at higher or lower temperatures, as needed. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature.
The resulting free amine can be acylated by treating the former with an acid or acid derivative, a base and an additive in a solvent. Specific examples of acids or acid derivatives include amino acids, sulfonic acid chlorides, carboxylic acid chlorides, carboxylic acid anhydrides, and carboxylic acids. More preferred are the following acid derivatives: acetyl chloride; methyl chloroformate; cyclopropyl acetyl chloride; methanesulfonyl chloride; N,N-dimethyl sulfamoylchloride; 3,3-dimethylbutanoyl chloride; morpholine carbamoyl chloride; furanoyl chloride; and 2-thiophenyl chloride. Specific examples of bases include TEA, diisopropylethylamine, pyridine, lutidine, and imidazole. Specific examples of additives include no additive, DMAP, EDCI, BOPCl, DCC, CDI, HATU, PyBOP and mixtures thereof. Specific examples of solvents include DCM, chloroform, diethyl ether, THF, dioxane, DMF, NMP and acetonitrile. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about four hours to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the free amine and TEA in about 0xc2x0 C. DCM were treated an acid chloride, warmed to room temperature and stirred for about 6 hours.
Or, the free amine can be reductively aminated by treating it with a carbonyl compound, a reducing agent, and an optionally added acid catalyst in a solvent. Specific examples of carbonyl compounds include aldehydes and ketones. More preferred is the following carbonyl compound, acetone. A specific example of an acid catalyst is AcOH. Specific examples of reducing agents include NaBH4 and NaCNBH3. Specific examples of solvents include THF, MeOH, EtOH and acetone. Although the reaction generally proceeds at room temperature, it can be run at lower or higher temperatures as needed. The reaction time is generally about two to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment the free amine in room temperature acetone was treated with NaCNBH3 and stirred for about 16 hours. 
As shown in Scheme 4, the conversion of (vii) to (viii) can be accomplished by treating the former with a hydroxylamine source and a base in a solvent. Specific examples of hydroxylamine sources include hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine nitrate, hydroxylamine phosphate and aqueous hydroxylamine. Specific examples of bases include TEA, DBU, pyridine, LiOH, NaOH, KOH, K2CO3, Na2CO3, and NaHCO3. Specific examples of solvents include ethanol, methanol, and isopropanol. Although the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperatures as needed. The reaction time is generally about eight hours to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (vii), hydroxylamine hydrochloride and K2CO3 were refluxed in ethanol for about 18 hours.
The conversion of (viii) to (ix) can be accomplished by treating the former with an acylating agent, and a base in a solvent. Specific examples of acylating agents include acid anhydrides and acid chlorides. More preferred is acetyl chloride. Specific examples of bases include TEA, diisopropylethylamine, pyridine, lutidine, and imidazole. Specific examples of solvents include acetone, THF, ethyl ether, DCM, chloroform and TBME. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures as needed. The reaction time is generally about 30 minutes to about 16 hours. In a particularly preferred embodiment, (viii) and TEA in room temperature acetone were treated with acetyl chloride and stirred for about one hour.
The conversion of (ix) to (x) can be accomplished by thermally cyclizing the former in a solvent. Specific examples of solvents include toluene, benzene, xylene, glyme, 2-butanone and NMP. Although the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperature as needed. The reaction time is generally about four hours to about 48 hours. In a preferred embodiment, (ix) in toluene was refluxed for about 24 hours. 
As shown in Scheme 5, the conversion of (vii) to (xi) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include LiOH, NaOH, KOH, K2CO3, and Na2CO3. Specific examples of solvents include THF, TBME, methanol, ethanol, water, and mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures as needed. The reaction time is generally about 30 minutes to about 24 hours. In a preferred embodiment, (vii), NH2OH.HCl, and K2CO3 in ethanol were refluxed for about 18 hours. 
As shown in Scheme 6, the conversion of (xii) and (xiii) to (xiv) can be accomplished by a palladium-mediated coupling as in Tetrahedron Letters, 1987, 28(45), 5395-5398, wherein X3 is a bromide, iodide or a triflate.
The conversion of (xiv) to (xv), wherein Z is a leaving group, can be accomplished by treating the former with a leaving group precursor and a base in a solvent. Specific examples of leaving group precursors include trifluoroacetic anhydride, trifluormethanesulfonyl chloride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of bases include, TEA, pyridine, lutidine, collidine, diisopropylethylamine, and DBU. Specific examples of solvents include THF, DCM, toluene, pyridine and chloroform. Although the reaction generally proceeds at 0xc2x0 C., it can be run at lower or elevated temperatures as needed. The reaction time is generally about 30 minutes to about 16 hours. In a preferred embodiment, (xiv) and TEA in 0xc2x0 C. THF were treated with para-toluenesulfonyl chloride and stirred for about 16 hours.
The conversion of (xv) and (vi) to (xvi) can be accomplished by combining (xv) and (vi) in the presence of a base, and an optionally added additive, in a solvent. R1, R2, and R3 are defined as in formula (I) and are substituents on the piperazine or diazepane ring. R4 is synonymous with R5 in this scheme and is defined in formula (I). Specific examples of (vi) include diamines such as piperazine, trans-1,4-diaminocyclohexane, 2-methylpiperazine, 2,6-dimethylpiperazine, trans-2,5-dimethylpiperazine, diazepane, and N,N-dimethyl-1,3-propanediamine. Specific examples of bases include K2CO3, Na2CO3, NaHCO3, K3PO4, LiOH, NaOH, and KOH. Specific examples of additives include KI, I2, and HI. Specific examples of solvents include acetone, 2-butanone, THF, DCM, and chloroform. Although the reaction generally proceeds at about 80xc2x0 C. it can be run at lower temperatures as needed. The reaction time is generally about 12 hours to about five days and can be selected depending on the reaction temperature. 
As shown in Scheme 7, the conversion of (xiii) to (xvii), wherein Z is a leaving group, can be accomplished by treating the former with a leaving group precursor and a base in a solvent. Specific examples of leaving group precursors include trifluoroacetic anhydride, trifluormethanesulfonyl chloride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of bases include, TEA, pyridine, lutidine, collidine, diisopropylethylamine, and DBU. Specific examples of solvents include THF, DCM, toluene, pyridine and chloroform. Although the reaction generally proceeds at 0xc2x0 C., it can be run at lower or elevated temperatures as needed. The reaction time is generally about 30 minutes to about 16 hours. In a preferred embodiment, (xiii) and TEA in 0xc2x0 C. THF were treated with paratoluenesulfonyll chloride and stirred for about 16 hours. 
As shown in Scheme 8, the conversion of (xvii) and (vi) to (xviii) can be accomplished by combining (xvii) and (vi) in the presence of a base, and an optionally added additive, in a solvent. R1, R2, and R3 are defined as in formula (I) and are substituents on the piperazine or diazepane ring. R4 is synonymous with R5 in this scheme and is defined in formula (I). Z is defined as a leaving group. Specific examples of (vi) include diamines such as piperazine, trans-1,4-diaminocyclohexane, 2-methylpiperazine, 2,6-dimethylpiperazine, trans-2,5-dimethylpiperazine, diazepane, and N,Nxe2x80x2-dimethyl-1,3-propanediamine. Specific examples of bases include K2CO3, Na2CO3, NaHCO3, K3PO4, LiOH, NaOH, and KOH. Specific examples of additives include KI, I2, and HI. Specific examples of solvents include acetone, 2-butanone, THF, DCM, and chloroform. Although the reaction generally proceeds at 80xc2x0 C. it can be run at lower temperatures as needed. The reaction time is generally about 12 hours to about five days and can be selected depending on the reaction temperature. 
shown in Scheme 9, the conversion of (xii) and (xviii) to (xvi) can be accomplished by a palladium-mediated coupling as in Tetrahedron Letters, 1987, 28(45), 5395-5398, wherein X3 is a bromide, iodide or a triflate.
The following preparative chemical examples of compounds of this invention are provided to enable those skilled in the art to carry out this invention. However, these examples are not to be read as limiting the scope of this invention as it is defined by the appended claims.